Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin-4-imines as potent 5-HT6 antagonists |
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| Institution: | 1. Bristol-Myers Squibb Research and Development, Discovery Chemistry, 5 Research Parkway, Wallingford, CT 06492, USA;2. Bristol-Myers Squibb Research and Development, Biology Neuroscience, 5 Research Parkway, Wallingford, CT 06492, USA;3. Bristol-Myers Squibb Research and Development, Pharmaceutical Candidate Optimization, 5 Research Parkway, Wallingford, CT 06492, USA;4. Bristol-Myers Squibb Research and Development, Computer Assisted Drug Design, 5 Research Parkway, Wallingford, CT 06492, USA;1. Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland;2. Jagiellonian University Medical College, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688 Kraków, Poland;3. Isobolographic Analysis Laboratory, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland;4. Department of Pathophysiology, Medical University, 8 Jaczewskiego Street, 20-090 Lublin, Poland;5. Department of Physiopathology, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland;6. Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland;7. Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland;1. Drug Discovery and Development Research Group, College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada;2. Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA;1. Research Group SynBioC, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium;2. Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, Faculty of Pharmaceutical Sciences, KU Leuven, O&N II Herestraat 49—box 921, 3000 Leuven, Belgium;1. Department of Bioorganic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;2. Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;3. Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;4. Laboratory of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;5. Department of Chemistry, Institute of Biology, Pedagogical University, Podchorążych 2, 30-084 Krakow, Poland;6. Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland |
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| Abstract: | Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2–4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure–activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability. |
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| Keywords: | Cognition Alzheimer’s disease Feeding behavior Obesity |
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